In this issue of “Small Molecule Highlights” we bring you 6 new small molecules out of recent drug discovery journals. These molecules target a diverse selection of targets, including GLP-1R, A1R, PI3K, mTOR, PLK4, and BRD4. Enjoy!
Compound 42: This dihydro-1,2,4-triazine has been reported as a glucagon-like peptide-1 receptor (GLP-1R) agonist. This metabolic hormone incretin is validated as a target in type 2 diabetes mellitus (T2DM). Inhibitor design was largely centered on the structural optimization of Danuglipron (with a focus on eliminating hERG liabilities). This was also coupled with structure-based strategies towards a potent agonist. In a HEK293 hGLP-1R cAMP assay, an EC50 of 6 pM was found, with a hERG IC50 of more than 40 μM. In vivo pharmacokinetic analyses (at 5 mg/kg, p.o. in rats) revealed a half-life of 1.05 hrs, and a maximal half-life of 0.25 hrs. Efficacy was also established in an OGTT study in hGLP-1R KI mice (1 mg/kg, o.g.) with an additional observation of the reduction of food intake.
Compound 7a: Urea-based 3,4-dichlorophenyl pyrazole was identified as an anti-microbial with inhibitory properties against S. aureus and M. tuberculosis. More specifically, activity was observed against MRSA, VRSA, TB, MDR-TB, and XDR-TB. Inhibitor design was focused on ligand-based strategies along with scaffold-hopping surrounding privileged azole motifs. Against S. aureus (ATC 29213), a MIC of 0.25 μg/mL was found, while against Mtb H37Rv (ATCC 27294), a MIC of 32 μg/mL was established. In vitro potency was observed against MSSA/MRSA (9 strains), VRSA (3 strains) with an average MIC of 0.25 μg/mL. In human liver microsomes (HLM), a half-life of T1/2 of 1.8 hrs was found, with an aqueous solubility (phosphate buffer, pH 7.4) of 0.005 mg/mL.
BD-9136: This tricyclic acetylene-based BET targeting PROTAC was reported as a degrader of BRD4. This BET domain protein is a histone reader, and transcription regulator, implicated in various diseases (especially cancer). Inhibitor design was focused on the conformational optimization of a known panBET inhibitor (QCA276) along with linker optimization. Against MV-4-11, MOLM-13, HL-60, and RS4;11 BRD4 DC50 values of 4.7, 1.5, 0.5, and 0.7 nM were found, while IC50 values of 11, 69, and 5.1 nM were reported for MV-4-11, MOLM-13, and HL-60. In vivo efficacy was also reported in both MV-4-11 and MD-MB-231 tumour models, with TGI values of 92% and 87%, respectively.
Compound 28c: This 3-methyl-tetrahydrofuran pyrimidine was found as an A1 adenosine receptor inhibitor. A1R is a GPCR, which signals via Gi/o proteins (implicated in various human diseases, including cancer). Inhibitor design involved a large-scale virtual screen (4.6 million analogs), followed by a rationally constructed enrichment funnel, and structure-based optimizations towards new A1R targeting structures. Docking studies (PDB 5UEN) suggested key H-bond interactions with several residues, including His, Asn, Phe, Thr, and Glu. Against A1R, a pKd of 8.64 was found (Kd of 2 nM), while a value of 6.76 was reported for A2R, representing a significant selectivity window (1.88 units).
FD274: This 7-azaindole based small molecule was identified as a PI3K/mTOR dual inhibitor, focused on targeting acute myeloid leukemia (AML). PI3K and mTOR are strong signal transduction kinases, which are highly implicated in various human cancers (especially haematological malignancies). Inhibitor design was focused on the structural optimization of previous inhibitor (FD223), along with scaffold-hopping strategies focused on establishing dual-inhibition (PI3K/mTOR). Against PI3Kα, β, γ, δ an IC50 of 0.7 nM, 1.6 nM, 0.7 nM, 0.4 nM was found, while against mTOR a value of 2 nM was established. Activity was also observed against HL-60, MOLM-13 and MV-4-11, with IC50 values of 84 nM, 53 nM, and 92 nM. In vivo efficacy was also observed in HL-60 tumour xenografts, at 10 mg/kg (i.p.), with a TGI of 91%.
SP27: This pyrimidine-2,4-difluorobenzylamine has been reported as a powerful degrader of polo-like kinase 4. PLK4 is a master regulator of centriole replication, and is widely implicated in human disease, especially in TRIM37 breast cancer. Inhibitor design involved a well-established PLK4i CZS-035 along with linker optimization studies and the introduction of a CRBN E3 ligase targeting binder. Against PLK4, an IC50 of 8.4 nM was found, and against MCF-7, a DC50 of 19.5 nM was reported (with an IC50 of 73 nM). Activity was also found in both a clonogenic and FACS apoptosis assay, as well as a wound-healing assay and a whole-proteome profiling chemoproteomic study (protein abundance). In vivo pharmacokinetic studies (2 mg/kg, i.v.) found a half-life of 5.34 hrs, with a mean residence time of 2.29 hrs with minimal activity observed against CYP enzymes. In vivo efficacy was also found in a MCF-7 xenograft tumour model (at 20 mg/kg, i.p.), with a TGI of 73.7%.